AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Alport syndrome encompasses a group of heterogeneous inherited disorders involving the basement membranes of the kidney and frequently involving the cochlea and the eye. These disorders are the result of mutations in type IV collagen genes. The mode of inheritance is X-linked in 80%, autosomal recessive in 15%, and autosomal dominant is reported in about 5% of individuals with Alport syndrome.

In 1927, Alport first described the combination of progressive hereditary nephritis with sensorineural deafness. The presence of 3 of the following 4 proposed diagnostic criteria establishes the diagnosis of Alport syndrome:

1. Family history of hematuria, progressing mostly in males to end-stage renal disease (ESRD)
2. Thickening and splitting of the glomerular basement membrane detected by electron microscopy
3. Progressive, high-frequency, sensorineural deafness
4. Anterior lenticonus and perimacular flecks

Children with Alport syndrome may initially present with only persistent hematuria and a family history of hematuria. Auditory or ocular manifestations may appear later in life. The typical changes of the glomerular basement membrane are also age dependent and may be absent from initial biopsy samples obtained from young children with Alport syndrome.

Pathophysiology

Recent advances in study of the cellular and molecular biology of proteins of the basement membrane have been instrumental in elucidating the pathophysiology of Alport syndrome. Basement membranes are sheetlike structures that support endothelial and epithelial cells. They are composed of various proteins that these cell secret, including a network of type IV collagen. The family of type IV collagens consists of 6 chains designated a1 through a6(IV) that share a collagenous domain and a carboxy-terminal noncollagenous (NC1) domain.

The genes for type IV collagen are distributed in pairs on 3 chromosomes. The genes COL4A1 and COL4A2 on chromosome 13 encode for the a1 and a2 changes, COL4A3 and COL4A4 on chromosome 2 encode for the a3 and a4 chains, COL4A5 and COL4A6 on the X chromosome encode for a5 and a6. The a1 and a2 chains are present in all basement membranes. The a3 and a4 chains are restricted to the basement membranes of the glomerulus, cochlea, and eye. The a5 chain is expressed in the glomerulus, cochlea, eye, and epidermis.

Patients with Alport syndrome have mutations in COL4A3, COL4A4, or COL4A5, with consequent abnormalities in the basement membranes of the glomerulus (leading to hematuria, glomerulosclerosis, and ESRD), cochlea (causing deafness), and eye (resulting in lenticonus and perimacular flecks).

Children with Alport syndrome usually have normal development and intelligence. However, a rare contiguous gene-deletion syndrome involving chromosome Xq22.3 was recently described; this has been named Alport syndrome and mental retardation (ATS-MR).

Frequency

United States

The genetic frequency for Alport syndrome is estimated to be 1 case in 5000 population. According to the 2005 annual data report of the United States Renal Data System, Alport syndrome accounts for approximately 2.5% of pediatric patients with ESRD.

International

In Europe, Alport syndrome may be responsible for as many as 2.3% of cases of ESRD.

Mortality/Morbidity

• Male individuals with X-linked Alport syndrome and both people of sexes with autosomal recessive disease have increasing proteinuria, hypertension, progression to ESRD, and hearing loss during the second to fourth decades of life.
• Male patients with the typical X-linked disease have a renal half-life of about 25 years, and about 90% develop ESRD before 40 years of age.
• In female patients, progression to ESRD was previously thought to be rare. However, recent observations have shown that as many as 12% of female patients also develop ESRD by the age of 40 years; this rate increases to 30% by the age of 60 years and 40% by age 80 years. Among female patients, risk factors for progression to ESRD include the degree of proteinuria and hearing loss.

Race

No racial predilection is reported.

Sex

• The common X-linked form of Alport syndrome leading to ESRD predominantly affects male individuals.
• Many female patients with X-linked Alport syndrome have mild disease, but recent studies have shown significant renal morbidity in female patients who develop proteinuria and hearing loss.
• The uncommon autosomal recessive form of Alport syndrome affects both sexes equally.
• See also Mortality/Morbidity above.

Age

• Most patients with Alport syndrome present with persistent microscopic hematuria and episodic gross hematuria during the first 2 decades of life.
• Two clinical subtypes of Alport syndrome have been distinguished on the basis of their rates of progression.
  • The first is a juvenile type in which ESRD occurs when an individual is approximately 20 years of age. Its course is fairly constant within a given family.
  • The second is an adult variety in which ESRD occurs when the individual is older than 40 years. This form has notable intrakindred variability.
• See also Mortality/Morbidity above.

CLINICAL

Section 3 of 11  

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History

• Hematuria
• • Hematuria is the most common presenting symptom.
  • Persistent microscopic hematuria is usually present from early childhood.
  • Episodic gross hematuria, at times precipitated by upper respiratory infections, is common during the first 2 decades of life.
  • Other renal manifestations are described in Physical.
• Hearing defect
• • Bilateral high-frequency sensorineural hearing loss usually begins by late childhood or early adolescence.
  • In the early stages of the disease, hearing loss is detectable only by means of audiometry.
  • As hearing loss progresses, it extends to the low frequencies, including those of human conversation, and patients require hearing aids.
  • About 50% of male patients with X-linked Alport syndrome show sensorineural deafness by 25 years of age, and about 90% are deaf by the age of 40 years.
• Ocular defect: Various ocular defects, including anterior lenticonus, perimacular flecks, and corneal ulceration, lead to increasing myopia and visual disturbances.
• Family history
• • In any child or adolescent with persistent microscopic hematuria, carefully seek a family history of hematuria, early-onset deafness, and renal insufficiency (especially in male patients).
  • In patients with typical clinical findings of Alport syndrome but a negative family history for the disease, suspect the autosomal recessive form.

Physical

• Renal findings
• • Hypertension usually is detectable by the second decade of life.
  • Edema and the nephrotic syndrome are not common in early childhood; however, the incidence progressively increases with age and is present in 30-40% of young adults.
  • With onset of renal insufficiency, symptoms of chronic anemia and osteodystrophy may become evident.
• Ocular findings
• • The anterior lenticonus is a regular conical protrusion of the central portion of the lens into the anterior chamber. With the exception of traumatic lenticonus, this lesion is pathognomonic for Alport syndrome. Anterior lenticonus predominantly affects males, it is frequently bilateral, and develops during the second decade of life. Anterior lenticonus may appear as an oil droplet during the red reflex, but formal ophthalmologic examination is usually required for early detection. Anterior lenticonus may be complicated by progressive distortion of the lens and subcapsular cataracts from rupture of the anterior lens capsule, leading to visual impairment. Anterior lenticonus is reported in About 25% of children with Alport syndrome. Patients with Alport syndrome and this finding usually progress to ESRD and deafness before 30 years of age.
  • The retinal changes of perimacular flecks affect 35% of individuals with Alport syndrome, but they are usually asymptomatic. The changes consist of a bilateral dot-and-fleck retinopathy resulting from superficial, densely packed, yellow-white granulations surrounding the foveal area. These lesions are specific for Alport syndrome.
  • Other uncommon lesions in persons with Alport syndrome include recurrent corneal ulceration and corneal endothelial vesicles.
• Cochlear findings
• • Bilateral high-frequency sensorineural hearing loss usually occurs by late childhood or early adolescence in individuals with Alport syndrome. This hearing loss is most prevalent and progressive in male patients with the disease.
  • In its early stages, hearing loss is detectable only on audiometry and only in the high-frequency range (ie, 2000- 8000 Hz). In 1 series, audiometry documented initial hearing loss in 85% of boys and male adolescents were younger than 15 years with Alport syndrome.
  • As hearing loss progresses, it extends to low frequencies, including those of human conversation, and its course roughly parallels the loss of renal function.
• Variants
• • An association of Alport syndrome with diffuse leiomyomatosis of the esophagus and tracheobronchial tree is reported in at least 26 families. These patients have typical X-linked Alport syndrome, usually the juvenile type, with a high incidence of cataracts. Female patients have vulvar and clitoral leiomyomatosis and other findings like those of male patients. Symptoms appear in late childhood and include dysphagia, postprandial vomiting, recurrent bronchitis, dyspnea, cough, and stridor.
  • An association between hereditary nephritis, deafness, and megathrombocytopenia is reported as part of 2 distinct syndromes. Fechtner syndrome consists of nephritis, sensorineural hearing loss, cataracts, macrothrombocytopenia, and characteristic polymorphonuclear inclusion bodies. Epstein syndrome is similar to Fechtner syndrome but without neutrophilic inclusions. Transmission appears to be autosomal dominant in both syndromes. Platelet abnormalities may be asymptomatic or cause hemorrhagic complications. Patients have normal expression of type IV collagen and no mutations in COL4A5. The specific genetic defects underlying these associations are now known. Mutations affecting nonmuscle myosin heavy-chain type II-A results in MYH9-related hereditary macrothrombocytopenia syndromes, including 4 autosomal dominant platelet disorders, ie, Fechtner, Epstein, May-Hegglin, and Sebastian syndromes.

Causes

• Approximately 50-80% of patients with X-linked Alport syndrome have mutations in the COL4A5 gene. Several hundred mutations, including missense mutations, splice-site mutations, and small deletions account for most cases of X-linked Alport syndrome. Few mutations have been found in more than 1 family.
• The most common mutation involves substitution for glycine in the collagenous domain of the a5(IV) chain by a bulky amino acid, resulting in protein-folding abnormalities.
• Other common mutations lead to premature termination of protein translation and loss of the carboxy-terminal NC1 domain, resulting in defective interchain association and formation of the collagen network.
• The X-linked Alport syndrome and the diffuse leiomyomatosis complex results from large deletion mutations in both COL4A5 and COL4A6. In contrast, patients with autosomal recessive Alport syndrome have mutations in COL4A3 and COL4A4.
• An incidental observation is that heterozygous mutations in COL4A3 and COL4A4 account for most cases of the relatively benign thin basement membrane disease. In some cases, mutations found in families with this disease are identical to those that cause autosomal recessive Alport syndrome in the homozygous or compound heterozygous forms.
• Patients with autosomal dominant Alport syndrome also have heterozygous mutations in the COL4A3 and COL4A4 genes

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Thin glomerular basement membrane disease
Urinary calculi
Berger nephropathy

WORKUP

Section 5 of 11  

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Lab Studies

• Urinalysis
• • In individuals with Alport syndrome, urinalysis reveals microscopic or gross hematuria. The urinary sediment is usually active, with dysmorphic RBCs indicating glomerular bleeding. RBC casts are occasionally observed.
  • Proteinuria is usually absent in the first few years of life but eventually develops in male patients with X-linked Alport syndrome and in people of both sexes with autosomal recessive disease. The degree of proteinuria usually increases with age and may reach the nephrotic range in 30-40% of young adults with Alport syndrome.
• Blood analysis
• • Blood counts and serum electrolyte, BUN, and creatinine levels reflect the degree of renal insufficiency.
  • Individuals with nephrotic syndrome may have clinically significant hypoalbuminemia and hypercholesterolemia.
  • Some patients with the autosomal dominant form of Alport syndrome also have thrombocytopenia, giant platelets, and granulocytic inclusions.

Imaging Studies

• Renal ultrasonography is indicated for children with persistent microscopic hematuria, primarily to exclude stone disease, cystic dysplasia, and other structural anomalies.
• Ultrasonographic findings are usually normal in individuals with early Alport syndrome. In late stages, the kidneys shrink symmetrically and progressively.

Other Tests

• Audiometry: All children with a history suggestive of Alport syndrome should undergo high-frequency audiometry to confirm the diagnosis (ie, high-frequency sensorineural hearing loss), as well as periodic monitoring.
• Ophthalmologic evaluation: Ophthalmologic examination is important for the early detection and monitoring of anterior lenticonus, perimacular flecks, and other eye lesions.

Procedures

• Renal biopsy
• • Percutaneous renal biopsy is an important part of the diagnostic workup. The test should be performed at a medical center equipped for ultrastructural analysis with electron microscopy. A medical center that has facilities for evaluating collagen chains of the basement membrane by means of immunohistochemistry is also desirable but not required.
  • Biopsy may be deferred in a patient with a strong family history of biopsy-proven Alport disease who presents with characteristic clinical features.
• Skin biopsy
• • Because the a5 chain of type IV collagen is also expressed in the epidermis, immunofluorescence examination of a skin biopsy specimen can be used to establish the diagnosis. Approximately 80% of male patients and 60% of female patients with X-linked Alport syndrome have no a5(IV) collagen in epidermal basement membrane. In addition, most individuals with autosomal recessive Alport syndrome do not express a3(IV), a4(IV), or a5(IV) collagens in skin. Healthy individuals and patients with thin-membrane disease, have normal expression of a5(IV) in the skin.
  • This approach is especially useful if a kidney biopsy poses an excessive risk, such as in patients with ESRD.
• Genetic analysis
• • Genetic analysis is the only means for diagnosing the carrier state in asymptomatic female individuals with a family history of X-linked Alport syndrome. Genetic analysis is also the only means for making a prenatal diagnosis.
  • Both linkage analysis and direct collagen-chain gene sequencing are performed in select research laboratories. However, screening for mutations in large collagen-chain genes is time consuming, and the current rate of identification of mutations in Alport kindreds is 50-80% at best.

Histologic Findings

On light microscopy, renal histologic findings are nonspecific. Abnormalities might not be observed in early Alport syndrome. With progression, increased mesangial matrix, segmental proliferation, and segmental sclerosis may appear. Conventional immunofluorescence studies of renal tissue usually yield negative results.

Electron microscopy reveals the characteristic lesions of Alport syndrome. glomerular basement membrane is irregularly thickened. The central lamina densa is split and splintered into a heterogeneous network of strands, which enclose electron-lucent areas that may contain microgranulations. The epithelial aspect of the capillary wall is irregular, and epithelial foot processes are fused. Thickening of the glomerular basement membrane is usually diffuse in adults with Alport syndrome, but in young children with the disorder, the thickening is segmental, and thinning of the basement membrane may be observed or even predominate. The degree of thickening increases with the patient's age and the degree of proteinuria. Therefore, a thick and split glomerular basement membrane is specific for Alport syndrome; however, its absence does not exclude the syndrome, especially in young children.

The basement membranes can be immunohistochemically evaluated by using monoclonal antibodies directed against the a3, a4, and a5 chains of type IV collagen. The absence of these chains in the glomerular basement membrane is characteristic of Alport syndrome. Because the a5 chain is also expressed in the epidermal basement membrane, skin biopsy is an additional tool for diagnosis. Male patients with X-linked Alport syndrome have a complete absence of a3, a4, and a5 chains in the glomerular and epithelial basement membranes, whereas female patients with X-linked disease have mosaicism and segmental loss of staining.

In patients with the autosomal recessive variety, glomerular basement membrane demonstrates no expression of the a3, a4, and a5 chains, but expression of the a5 chain is present in the epidermal basement membrane. These observations suggest that a mutation affecting 1 of the chains can affect the expression of all 3 chains, perhaps because of degradation of normal chains that have not assembled into functional trimers.

TREATMENT

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Medical Care

• No treatment prevents the progression to ESRD in male patients with X-linked Alport syndrome or in patients with autosomal recessive disease.
• • Some data suggests that cyclosporine therapy or angiotensin-converting enzyme (ACE) inhibitors decrease proteinuria and may slow the rate of progression.
  • Recent abstracts suggest that the response to cyclosporine can be variable and that cyclosporine may accelerate the development of interstitial fibrosis. Therefore, such therapy should be approached with caution and with close monitoring.
• Begin appropriate replacement therapy as renal failure advances. Therapy includes erythropoietin for chronic anemia, phosphate binders and vitamin D to manage osteodystrophy, alkali to correct acidosis, and antihypertensive therapy to control blood pressure.
• Hemodialysis or peritoneal dialysis does not raise specific problems.

Surgical Care

• Renal transplantation is the treatment of choice for ESRD in individuals with Alport syndrome. The results of renal transplantation for patients with Alport syndrome compare favorably with results in persons with other diagnoses.
• About 3-5% of male patients with transplants develop anti-glomerular basement membrane glomerulonephritis. These individuals usually have early-onset Alport syndrome with clinically significant hearing loss and ESRD by about20 years of age.
• • The pathogenesis is related to the donor glomerular basement membrane with antigens that the recipient lacked; therefore, the recipient never develops immune tolerance to these antigens. These anti–glomerular basement membrane antibodies are directed against the NC1 domain of a5(IV) chain in patients with X-linked Alport syndrome and against the NC1 domain of a3(IV) chain in individuals with autosomal recessive disease.
  • Anti–glomerular basement membrane disease generally begins within the first year after transplantation. Individuals with this disease develop a severe crescentic-type glomerulonephritis, and 75% of the allografts fail within a few weeks. Plasmapheresis and cytotoxic agents have been of limited value.
  • Anti–glomerular basement membrane glomerulonephritis commonly recurs in patients who receive more than 1 transplant despite prolonged intervals between transplantations and despite an absence of circulating anti–glomerular basement membrane antibodies before retransplantation.
• Female patients with X-linked Alport syndrome and all patients with healthy hearing or late progression to ESRD have a low risk for anti-glomerular basement membrane disease after transplantation.
• Given the typically good rate of graft survival in patients with Alport syndrome and given the inability to predict rare anti–glomerular basement membrane disease after transplantation, the use of living donor organs is generally recommended. The feasibility of using kidneys obtained from female donors who do not have symptoms of Alport syndrome and who are heterozygous for COL4A5 mutations is unresolved.

Consultations

• Pediatric nephrologist
• Ophthalmologist
• Audiologist
• Transplant surgeon
• Genetic counselor

Diet

• Asymptomatic patients require no dietary restrictions.
• Individuals with hypertension benefit from a low-salt diet.
• Protein restriction is routinely prescribed for adults with proteinuria and diminished renal function. The utility of restricting protein intake in a growing child with high protein requirements has not been established.

Activity

In general, no restriction of activity is indicated for individuals with Alport syndrome.

MEDICATION

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Drug Category: Immunosuppressive agents

Cyclosporine may reduce proteinuria and retard the progression of renal disease by inducing afferent arteriolar vasoconstriction, increasing glomerular permselectivity, and inhibiting proinflammatory lymphokines. Efficacy of this treatment in patients was documented only in small series, and further studies are required before this therapy can be recommended on a routine basis. Recent abstracts suggest that cyclosporine may accelerate the development of interstitial fibrosis. Therefore, such therapy should be approached with caution and with close monitoring.

Drug Category: ACE inhibitors

These drugs may reduce proteinuria and retard the progression of renal disease by decreasing hydrostatic pressure across glomerular capillaries. Preliminary studies demonstrated effectiveness and relative safety of ACE inhibition in children with Alport syndrome, and its cautious use now is recommended.

FOLLOW-UP

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Further Inpatient Care

• Admit patients with acute complications of renal failure or those needing renal-replacement therapy.
• Admit patients who are undergoing renal transplantation.

Further Outpatient Care

• Monitor medication doses and adverse effects.
• Monitor renal function and the degree of proteinuria on a yearly basis.
• Perform audiometry and ophthalmologic evaluations once every 2 years.

In/Out Patient Meds

• Cyclosporine may decrease proteinuria and slow the rate of progression to ESRD.
• ACE inhibitors also may decrease proteinuria and slow the rate of progression to ESRD.

Transfer

• Renal biopsy should be performed at a center with experience in pediatric biopsy and with facilities for ultrastructural analysis.
• Transfer of the patient to a dialysis unit is indicated to manage peritoneal dialysis or hemodialysis.
• Transplantation should be performed at a center with experience in pediatric kidney transplantation.

Complications

• ESRD: Renal failure develops in male patients with X-linked Alport syndrome and in patients with autosomal recessive disease.
• Hearing loss
• Visual loss

Prognosis

• The renal prognosis for male patients with X-linked Alport syndrome and for all patients with autosomal recessive disease is poor, with most progressing to ESRD.
• • Patients with a family history of juvenile-type Alport syndrome or with early-onset deafness and ocular changes typically progress to ESRD by the age of 20-30 years.
  • Male patients with the typical X-linked disease have a renal half-life of about 25 years, and about 90% develop ESRD before 40 years of age.
  • The degree of proteinuria is predictive of the rate of progression.
• The long-term prognosis for female patients with X-linked Alport syndrome is generally more benign than that of male patients, with many surviving to old age with clinically mild renal disease.
• • Recent observations have shown that as many as 12% of female patients also develop ESRD by the age of 40 years; this rate increases to 30% by the age of 60 years and 40% by the age of 80 years.
  • Among female patients, risk factors for the progression to ESRD include the degree of proteinuria and hearing loss.

Patient Education

• Screen family members for subclinical microscopic hematuria.
• In asymptomatic patients, stress the importance of yearly physical examinations and laboratory evaluations. Advise patients to receive audiometry and visual testing every 2 years.
• Advise parents affected with Alport syndrome and potential carriers of the disorder to obtain genetic counseling.
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Blood in the Urine.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to consider Alport syndrome in an asymptomatic patient who has persistent microscopic hematuria
• Failure to recognize that renal biopsy findings in individuals with early Alport syndrome may be indistinguishable from findings of thin glomerular basement membrane disease
• Failure to recognize that genetic analysis reveals specific mutations in only 50-80% of individuals with Alport syndrome
• Failure to counsel patients about the genetic implications of Alport syndrome on their future progeny and failure to advise the parents and relatives of an individual with the disorder

Special Concerns

• In women with the more severe form of Alport syndrome, pregnancy may accelerate the progression to ESRD.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Electron micrograph from a patient with Alport syndrome revealing the typical splitting and splintering of the glomerular basement membrane (original magnification X3000). Courtesy of Glen S. Markowitz, MD, Department of Pathology, Columbia University College of Physicians and Surgeons, New York.
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Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Jul 11, 2006